Design, Synthesis, Evaluation, and Crystallographic-Based Structural Studies of HIV-1 Protease Inhibitors with Reduced Response to the V82A Mutation

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• 作者：José ; C. Clemente ; Arthur Robbins ; Paula Grañ ; a ; M. Rita Paleo ; Juan F. Correa ; M. Carmen Villaverde ; F. Javier Sardina ; Lakshmanan Govindasamy ; Mavis Agbandje-McKenna ; Robert McKenna ; Ben M.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：February 28, 2008
• 年：2008
• 卷：51
• 期：4
• 页码：852 - 860
• 全文大小：678K
• 年卷期：v.51,no.4(February 28, 2008)
• ISSN：1520-4804

文摘

In our quest for HIV-1 protease inhibitors that are not affected by the V82A resistance mutation, we have synthesized and tested a second generation set of C₂-symmetric HIV-1 protease inhibitors that contain a cyclohexane group at P1 and/or P1′. The binding affinity results indicate that these compounds have an improved response to the appearance of the V82A mutation than the parent compound. The X-ray structure of one of these compounds with the V82A HIV-1 PR variant provides the structural rationale for the better resistance profile of these compounds. Moreover, scrutiny of the X-ray structure suggests that the ring of the Cha side chain might be in a boat rather than in the chair conformation, a result supported by molecular dynamics simulations.